Effects of Phenobarbital on the Synthesis and Degradation of the Protein Components of Rat Liver Microsomal Membranes

The synthesis and turnover of the total proteins of endoplasmic reticulum membranes and of two enzymes, i.e. NADPH-cytochrome c reductase and cytochrome b5, isolated and purified from these membranes, have been studied during treatment with phenobarbital, one of the drugs known to induce an increase in the activity of hydroxylating enzymes and in the amount of smooth endoplasmic reticulum membranes in rat hepatocytes. A single phenobarbital dose induces a prompt increase in the rate of NADPH-cytochrome c reductase synthesis without affecting the production of cytochrome b5. The induced reductase is chromatographically and immunochemically identical with the enzyme normally produced by the liver. Repeated phenobarbital doses cause a large increase in NADPH-cytochrome c reductase amount concomitantly with a moderate rise in cytochrome b5 content. Both effects appear to result from a drastic reduction in rates of enzyme degradation. Cessation of phenobarbital treatment is promptly followed by a progressive reduction in NADPH-cytochrome c reductase amount caused by a large increase in the rate of degradation of the enzyme in the face of continued synthesis. The findings indicate that the rates of synthesis and degradation of the NADPH-cytochrome c reductase vary conversely in the induction process. The relevance of these findings to the control of the turnover of membrane enzymes is discussed.